A living vascular prosthesis that experiences growth and adaptation, remains patent, and has life-long functionality, thereby completely replacing the diseased vessel with a healthy alternative, is the Holy Grail for vascular surgery; however, such prosthesis particularly for small-diameter vessels are currently unavailable. Hence, this proof of principle proposal is to establish a simple and efficient approach for the regeneration of small diameter arteries in vivo. Our central hypothesis is that an inhibitor of a transcription-regulating enzyme CDK8 (cyclin-dependent kinase 8) could transform decellularized vessel scaffolds into mature arteries; i.e., the regeneration of small-diameter arteries in vivo. Delivery of the drug is achieved using a semi-viscous, bioengineered, biocompatible, and biodegradable Alginate/PLGA system applied perivascularly during the grafting process. The underlying rationale comes from our pilot studies indicating that: 1) Targeting vascular stem cells (VSCs) residing in decellularized vessel scaffolds by perivascular delivery of CDK8 inhibitor Senexin A for 3 days immediately after transplantation facilitates arterial transformation of the vessel grafts. 2) A Senexin A-coated synthetic degradable polymer could maintain the effective concentration of Senexin A up to 2 weeks in a hydrophobic environment. Accordingly, our hypothesis will be tested by 2 specific aims as follows: Aim 1. To characterize the effect of perivascular delivery of Senexin A on the transformation of decellularized vessel scaffolds into arteries. Aim 2. To establish the efficacy of optimized Senexin A perivascular delivery using well-characterized, degradable, biomaterials for the transformation of decellularized vessel scaffolds into arteries. This proposed work will establish for the first time a simple and efficient approach for the regeneration of small-diameter arteries in vivo, providing a novel concept, i.e., a decellularized vessel scaffold with proper integration of regenerative signals for controlling VSCs homing and differentiation could lead to a complete regeneration of mature vessels in vivo and initiating a new venue of bioengineering vascular implants for vessel regeneration.